DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/09/2025 has been entered.
Response to Amendment
Applicant’s response of 03/25/2025 has been received and entered into the application file. Claims 1-34 and 36 are pending in this application. New claim 36 is added.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-10, 13-17, 18, 21-34 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Slager et al. (US 8,883,208 B2, 2014), Schneider et al. (Applications of EVA in drug delivery systems, Journal of Controlled Release, 2017), MatWeb (Overview of materials for EVA, Film Grade, Website established 2011), Huysmans et al. (Improving the Repeatability and Efficacy of Intradermal Electroporated Self-Replicating mRNA, Molecular Therapy: Nucleic Acids, 2019), and Almeida et al. (Sustained release from hot-melt extruded matrices based on ethylene vinyl acetate and polyethylene oxide, European Journal of Pharmaceutics and Biopharmaceutics, 2012) further evidenced by Jong et al. (Controlled release of plasmid DNA, Journal of Controlled Release, 1997).
Slager et al. teach devices and methods for the release of nucleic acid complexes. The delivery particle can include a polymeric matrix including a polyethyleneglycol containing copolymer and a nucleic acid complex disposed within the polymeric matrix. The nucleic acid complex can include a nucleic acid and a carrier agent. The invention includes implantable medical device comprising nucleic acid complex within a polymeric matrix (Abstract). Slager et al. teach nucleic acids used can include various types of nucleic acids that can function to provide a therapeutic effect (col 4, lines 1-5). Suitable polymers include poly(ethylene-co-vinyl acetate) having vinyl acetate concentrations of between about 10% and about 50% (col 19, lines 34-36). Slager et al. teach the multi-block polymers can have temperature of approximately 37 degrees Celsius (col 7, lines 1-3).
Slager et al. do not specifically mention the ratio of the melting temperature of the carrier to the ethylene vinyl acetate copolymer.
Schneider et al. teach that ethylene vinyl acetate (EVA) is used in many drug delivery systems (Table 1, and Introduction paragraph). Schneider et al. teach that crystallinity, melting point, stiffness and polarity of the EVA is determined predominantly by the VA content. EVA at zero VA content has a melting temperature range of 110-120 degree Celsius. Melting temperature of EVA decreases with increasing VA concentration, leading to an amorphous, soft polymer with a broad melting point of 45-55 degree Celsius at 40 wt.% vinyl acetate (page 285, Properties of EVA). Schneider teaches that delivering DNA or RNA in vivo has been found to be difficult due to rapid degradation of nucleic acids in the body. One approach to deliver nucleic acids at high translation efficacies might be through embedding lyophilized DNA or RNA in an EVA matrix. Implants created in this way exhibit sustained release of functional nucleic acid with the ability to transduce or translate cells. In studies, small Herring sperm DNA, large molecular weight plasmid DNA as well as naked and lipofectamine complexed plasmid DNA were released in vitro over time frames of several days up to 6 months. EVA implants pioneered by Langer and Folkman enable sustained delivery of a wide variety of biological molecules (page 292, left col). One of ordinary skill in the art would be motivated to combine any and all types of nucleic acids within EVA based implants.
Slager et al. and Schneider et al. do not teach melt flow index of EVA.
MatWeb (Overview of materials for EVA, Film Grade) teaches the original value of melt flow index of ethylene vinyl acetate of 0.190-135 g/10 min. The range is well within what is claimed in claim 1. Furthermore, one of ordinary skill in the art would, through routine experimentation, experiment with different melt flow index of ethylene vinyl acetate. And it would have been obvious to do so in this instant case.
Above references do not specifically mention ribonuclease inhibitors.
Huysmans demonstrates that local administration of naked self-replicating mRNA in the skin or muscle with a protein-based RNase inhibitor increased the expression efficiency, success rate, and repeatability of data (Abstract).
Almeida discloses the importance of matrix flexibility of hot-melt extruded ethylene vinyl acetate matrices. In some models, polyethylene oxide was used as a swelling agent. The processability via HME and drug release profiles of EVA/MPT/PEO formulations were assessed. The processability of HME varied according to the VA content: EVA 40 and 28 were extruded at 90 degrees Celsius, whereas higher viscosity EVA grades required a higher temperature. Drug release from EVA matrices depended on the VA content, matrix porosity, pore size distribution (Abstract). In Fig. 2., Almeida discloses that active agent, metoprolol, released from EVA without PEO showed a cumulative drug release of ~40-50% over 24 hours which plateaus onward (See Fig. 2).
One of ordinary skill in the art would experiment with an implantable medical device comprising nucleic acid, carrier, and polymer matrix such as EVA with various wt. % of vinyl acetate. As discussed above, depending on the concentration of vinyl acetate, the melting temperature of the EVA polymer can be manipulated. Furthermore, the use of EVA polymer as a drug delivery device is well-established and many commercial products are available on the market (see Schneider’s et al. Tables 1 and 2). Furthermore, the melt flow index is within the original value as taught by MatWeb. Huysmans teaches that RNase inhibitor with mRNA increased the expression efficiency and success rate. Almeida teaches that drug release depends on many routinely experimented factors such as VA content, matrix porosity, and pore size distribution. Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined an implantable medical device comprising carrier and encapsulated nucleic acid within EVA copolymer with specific melting temperature profile to deliver nucleic acid over a prolonged period of time. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 2, Schneider et al. teach that the drug release could be readily customized via the blend ratio of the polymers (page 289, 1st paragraph). Furthermore, one of ordinary skill in the art would experiment with various weight ratios.
Regarding claim 3, melting temperature of ethylene vinyl acetate copolymer is discussed above.
Regarding claim 4, Schneider et al. teach many EVA polymer pharmaceutical products as discussed above. Furthermore, one of ordinary skill in the art would experiment with EVA polymer as the only content of the polymer matrix.
Regarding claim 5, in some embodiments, Slager et al. teach mixing nucleic acid delivery particles, a first polymer, and a solvent/plasticizer to form a coating solution (col 1, lines 62-65).
Regarding claims 6-7, poly(ethylene-co-vinyl acetate) is discussed above. Furthermore, Schneider et al. teach that a number of active ingredients have ben studied in conjunction with EVA for implantable dosage forms (page 288, Implantable dosage form section).
Regarding claim 8, Slager et al. teach suitable polymers include poly(ethylene-co-vinyl acetate) having vinyl acetate concentrations of between about 10% and about 50% (col 19, lines 34-36).
Regarding claim 9, one of ordinary skill in the art would experiment with different melt flow index of polymers. Furthermore, the melt flow index value as claimed is within the normal physical melt flow ranges as shown in MatWeb (See NPL attached).
Regarding claim 10, Slager et al. teach the nucleic acids can be ribonucleic acids, deoxyribonucleic acids (col 4, lines 1-10).
Regarding claim 13, Slager et al. teach spherical implant when viewed in cross-section (col 3, lines 9-10).
Regarding claims 14-16, Slager et al. teach that the delivery device can take on many different forms including a filament, cylinder, irregular shape or the like (col 3, lines 50-53). Furthermore, one of ordinary skill in the art would, through routine experimentation, experiment with different shapes and diameters of an implantable device.
Regarding claim 18, one of ordinary would experiment with different excipients such as RNA degradation inhibitor. An implantable device delivering RNA would benefit from RNA degradation inhibitor because RNA degradation inhibitor would prevent degradation of RNA. And it would have been obvious to do so in this case.
Regarding claim 21, Slager et al. teach natural or naturally-based polymers can include polysaccharides and modified polysaccharides such as starch, cellulose, chitin, chitosan, and copolymers thereof (col 9, lines 43-46).
Regarding claim 22, Slager et al. teach that the polymers can have hydrophilic polymers such as PEG block (col 6, lines 8-10).
Regarding claim 23, hydrophilic polymers are discussed above.
Regarding claim 24, Slager et al. teach formation of microparticles with various polymer blends (Table 1). Furthermore, one of ordinary skill in the art would experiment with different weight % ratios of particles to polymers for an implantable medical device. And it would have been obvious to do so in this instant case.
Regarding claim 25, Slager et al. teach that the drug delivery device can cover the drug release layer as shown in Figure. 2.
Regarding claim 26, Slager et al. teach that the particles are disposed within a matrix, forming an active agent delivery device (col 3, lines 15-22, also see Fig. 2).
Regarding claims 27-29, hydrophobic polymer such as ethylene vinyl acetate is discussed above.
Regarding claim 30, hydrophilic compounds are discussed above.
Regarding claim 31, Slager discloses siRNA/peptide release from particles over time (See Fig. 6). Likewise, one of ordinary skill in the art would experiment with how much naked nucleic acid is released rom the implantable medical device.
Regarding claim 32, Slager et al. teach the polymer blends through an extruder or mixer (col 24, lines 16-20). Furthermore, Schneider et al. teach that EVA is most commonly processed by hot-melt extrusion (page 286, 1st paragraph). Additionally, hot-melt extrusion method is routinely used for EVA implants as discussed above.
Regarding claim 33, hot-melt extrusion methods can comprise performing at various temperatures and one of ordinary skill in the art would experiment with different temperature ranges. And it would have been obvious to do so in this instant case.
Regarding claim 34, Schneider et al. teach that an implantable device is extruded using a small single screw extruder (page 288, left column, Subcutaneous implants section). Furthermore, one of ordinary skill in the art would experiment with different screw sizes to perform hot-melt extrusion. And it would have been obvious to do so in this instant case.
Regarding claim 36, Jong discloses that plasmids and herring sperm DNA were encapsulated in EVA. The bioactivity of the released plasmid DNA was assessed. Extraction of plasmid DNA from the delivery systems indicated that the fabrication conditions did not degrade the DNA. Depending on initial DNA loading, detectable levels were released for 1-6 months. Conformational analysis of released plasmid DNA showed DNA was released without degradation and retained the ability to transfect cells in vitro. The results demonstrated that controlled release systems can be fabricated for the release of very large molecular weight plasmid DNA (Abstract). One of ordinary skill in the art would immediately envisage that a naked nucleic acid such as plasmid can be delivered by polymers.
Claims 11-12, 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Slager et al. (US 8,883,208 B2, 2014), Schneider et al. (Applications of EVA in drug delivery systems, Journal of Controlled Release, 2017), MatWeb (Overview of materials for EVA, Film Grade, Website established 2011) Huysmans et al. (Improving the Repeatability and Efficacy of Intradermal Electroporated Self-Replicating mRNA, Molecular Therapy: Nucleic Acids, 2019), and Almeida et al. (Sustained release from hot-melt extruded matrices based on ethylene vinyl acetate and polyethylene oxide, European Journal of Pharmaceutics and Biopharmaceutics, 2012) as applied to claims 1-10, 13-18, 21-34 and 36 above, and further in view of Almarsson et al. (US 2018/0085474 A1).
Teachings of Slager et al. and Schneider et al. are discussed above.
Almarsson et al. teach nanoparticle compositions including an mRNA and a lipid component and methods of using the same (Abstract). A polymer may be included in and/or used to encapsulate mRNA, such as ethylene vinyl acetate polymer (EVA) ([0056]).
Almarsson et al. teach that mRNA and lipids are combined with polymers such as EVA for delivery of such composition into subjects in need. Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have chosen mRNA as the nucleic acid for delivery via an implantable medical device. This is combining prior art elements according to known methods to yield predictable results such as an implantable device comprising a specific nucleic acid such as mRNA.
Regarding claim 12, one of ordinary skill in the art would recognize that mRNA could comprise reading frames that would encode at least one antigenic polypeptide depending on what reading frames are incorporated. And it would have been obvious to do so in this instant case.
Regarding claim 19, Almarsson et al. teach that additional agents can include chelating agents ([0063]).
Regarding claim 20, Almarsson et al. teach the nanoparticle composition to include permeability enhancing molecules ([0022]).
Response to Arguments
Applicant’s arguments filed 07/09/2025 have been fully considered and new rejections are applied above. Applicant argues that the reference of record do not teach the cumulative release after a time period of at least 7 days. This is found persuasive and, therefore, the Almeida reference has been added to the rejection to provide that teaching.
Conclusion
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615